This application addresses the FY11 PRMRP Topic Area, Epidermolysis Bullosa, and proposes to develop stem-cell based therapies for junctional epidermolysis bullosa JEB, which is one of the most severe forms of epidermolysis bullosa EB, a group of rare inherited skin blistering diseases. To accomplish this goal, we are proposing to develop stem-cell based therapies for EB using autologous induced pluripotent stem cells iPSCs derived from skin cells harvested from the same EB patient. During the second year of funding, we developed a novel integration-free protocol for the reprogramming of human primary fibroblasts and keratinocytes into clinically relevant iPSCs. The efficiency of our method surpasses all previously published reports and results in the generation of stable iPSC lines. The protocol was employed for the reprogramming of human JEB fibroblasts into iPSCs, which now allows us to address the possibility of gene correction via ZFNs in these human JEB iPSCs. Our developed iPSC generation protocol is applicable not only to JEB patients but also to patients with other inherited skin diseases, as well as veterans with chronic wounds. In addition to reprogramming, we have further optimized our method for the differentiation of iPSCs into keratinocytes, thus fulfilling major prerequisites for the successful accomplishment of the proposed study.